期刊
MOLECULAR NEUROBIOLOGY
卷 55, 期 2, 页码 1338-1351出版社
HUMANA PRESS INC
DOI: 10.1007/s12035-017-0396-7
关键词
Angiogenin; Progranulin; Neurodegeneration; TiRNA; Apoptosis
资金
- National Natural Science Foundation of China [31570786, 81372303, 81601101, 31400648]
Gene defects have been recognized as prominent factors in the etiology and pathogenesis of neurodegeneration. Among 60 neurodegeneration-related mutations in progranulin (PGRN), a mutation in PGRN gene exon 1 introduces a charged amino acid in the hydrophobic core of its signal peptide at residue 9 (named PGRN A9D) and results in incorrect cytoplasmic sorting. However, the pathogenesis of this mutation remains elusive. To address this issue, we first examined the subcellular distribution of PGRN A9D in human neuronal-like cells (SH-SY5Y). The results showed that PGRN A9D accumulated in cytosolic stress granules. Interestingly, this mis-sorting associated with a cellular redistribution of angiogenin (ANG), a stress-response factor and neurodegenerative disease-related protein, from nucleus to cytoplasmic stress granules, and there existed protein interaction between PGRN A9D and ANG. Further study revealed that the stress granule localization of PGRN A9D was dependent on ANG. Functionally, PGRN A9D abolished the nuclear ANG-mediated biological roles; on the other hand, the relocation of ANG to stress granules activated its cytoprotective stress-response program by cleaving transfer RNAs (tRNAs) to tiRNAs (tRNA-derived, stress-induced small RNAs), thus promoting PGRN A9D cell survival. Taken together, we hypothesize that PGRN A9D leads to the retention of ANG in the cytoplasm to protect cells from PGRN A9D-induced apoptosis, implying that PGRN and ANG act in concert to regulate the progress of neurodegenerative disease.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据